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Molecular Mechanisms Controlling Excitatory Synaptic Transmission 10.17863/CAM.39689 Watson, Jake Frederick 0000000286983823 Greger, Ingo 0000000272912581 At synapses, the sites of communication between neurons, neurotransmitter is released from the presynaptic cell and binds to postsynaptic receptors on another. In the case of excitatory synapses, the predominant neurotransmitter, L-glutamate, binds to postsynaptic AMPA receptors (AMPARs). Crucially, synaptic strength is plastic, and control of this strength is essential for fundamental brain functions such as the processing and storage of information. Synaptic transmission is controlled by tuning the response of postsynaptic receptors to glutamate release. This can be achieved by altering both the number and spatial positioning of receptors. The mechanisms governing AMPAR anchoring at postsynaptic sites have been intensely studied for many years, focussing on intracellular interactions with postsynaptic scaffold proteins, however, these interactions do not appear strictly essential to synaptic receptor anchoring. The receptor’s N-terminal domain (NTD) comprises 50 % of the protein, and extends into the synaptic cleft, towards the presynapse, offering great potential for subunit-specific receptor control, yet its influence on synaptic transmission remains elusive. Facilitated by the development of an optimised molecular cloning approach, this study uses a combination of electrophysiological and imaging methods to investigate the role of the AMPAR NTD at synaptic sites. It demonstrates that this domain has a critical role in anchoring the AMPAR at the synapse. Through subunit-specific interactions in the synaptic cleft, the NTD controls the number of receptors present at a synaptic connection. Receptors lacking the NTD are unable to properly anchor at synaptic sites, and are unable to facilitate synaptic plasticity such as long-term potentiation, despite robustly trafficking to the cell surface. When studied in comparison to other AMPAR anchoring interactions, NTD-dependent mechanisms appear to be more influential than classical models involving the intracellular C-terminal of the receptor. Given that NTD-dependent interactions will occur within the synaptic cleft, both pre and postsynaptic neurons have the potential to control and detect the strength of synaptic transmission. Therefore, this mechanism of AMPAR anchoring has profound implications when considering how information is stored at a synaptic connection. University of Cambridge 2019-07-19 Thesis Doctoral Doctor of Philosophy (PhD) en This thesis was funded by a Medical Research Council Studentship. https://www.repository.cam.ac.uk/handle/1810/292529 https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/292600ab-6f22-4e9a-991e-6775d38f47c1/download 3e43fa77295f7b43ec8c4425a27106c2 https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/ee0e5161-af2d-44fc-914c-b837b48eae4e/download 87eda9de84448d1f82354d60eee3eb5f https://www.rioxx.net/licenses/all-rights-reserved/ AMPA receptor AMPAR LTP long-term potentiation synaptic plasticity synaptic transmission glutamate glutamate receptors iGluRs